Bromodomains are protein domains of biological and pharmaceutical interest, for example as components of transcription factor complexes and determinants of epigenetic memory. The human genome codes for 61 bromodomains that are present in 46 human proteins, and which may be categorized into 8 distinct bromodomain families based on primary sequence conservation (Nat Rev Drug Discov. 2014 May; 13(5):337-56). One such family, the BET family, or bromodomain and extraterminal domain family, includes BRD2, BRD3, BRD4 and BRDT all of which are found in humans. Bromodomains are capable of recognizing acetylated histones. The BET family has a common domain architecture featuring two amino-terminal bromodomains that exhibit high levels of sequence conservation, and a more divergent carboxy-terminal recruitment domain (Filippakopoulos, P. et al., Nature 2010, 468, 1067-1073). BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008, 30, 51-60). It has also been reported that BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes in a highly malignant form of epithelial neoplasia called NUT-midline carcinoma. It has been suggested that BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene 2008, 27, 2237-2242). BRDT is uniquely expressed in the testes and ovary.
All BET family members have been reported to have some involvement in aspects of the cell cycle. In addition, some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al. Cell 2004 117, 349-60). BRD4 appears to be involved in the recruitment of the pTEF-P complex to inducible genes resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell 2009 138, 129-145).
In recent years, proteins containing bromodomains have attracted much interest and bromodomain binding agents have been reported in WO2009084693, WO2012075383, WO2011054553, WO2011054841, WO2011054844, WO2011054845, WO2011054846, WO2011054848, WO2011143669, WO2011161031, WO2013027168, WO2014095774, and WO2014095775.
Thus proteins containing bromodomains have been reported to be involved in transcription, DNA repair, replication, and chromosome condensation. Filippakopoulos, P. et al. recently published a review summarizing many findings related to proteins containing bromodomains (Filippakopoulos, P. et al., Nature Reviews Drug Discovery, 2014, doi:10.1038/nrd4286).
Despite the progress in the field of molecules that modulate the function of bromodomains there is a need for further bromodomain inhibitors.